ANVISA

New Regulatory Framework for APIs

Gabriel Ramos Ferronatto

Overview

RDC 359/2020 RDC 361/2020 RDC 362/2020

• Primarily intended for DIFA • Primarily intended for MA • Defines the criteria for GMP
holders applicants/holders certification of foreign API
• Alters: manufacturers
• DIFA
• DIFA holder • RDC 200/2017
(marketing
• CADIFA
authorisation
• Submission procedure applications)
• API-related changes • RDC 73/2016
(variations to marketing
• Suspension/Withdrawal
authorisations)

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Timeline

Mandatory for APIs that were subject to API Registration*

Optional if the DP batches

Optional are manufactured until T2. Mandatory
Or else, mandatory.

T0 T1 T2 T3
April 2020 August 2020 February 2022 August 2023
(publication) (in effect)

T1’ Transition period

March 2021

*APIs listed in IN 15/2009 & IN 3/2013

Main aspects

1. Centralised assessment

2. Single Resolution for APIs (RDC 359/2020)

3. Direct communication with DIFA holders (Brazilian or foreign)

4. International harmonization through adoption of ICH guidelines

(*pertaining to APIs*)

5. Mandatory audit conducted by the Marketing Authorisation

Holder/Applicant (RDC 301/2019 & RDC 361/2020)

6. GMP Certification/Inspections (RDC 362/2020)

Centralised assessment / Single Resolution

Before
New Policy
& Transition period

MA applications MA applications
DP + API DP
(RDC 200/2017) (RDC 200/2017)

Variations to MAs Variations to MAs

DP + API DP
(RDC 73/2016) (RDC 73/2016)

API Registration
API
Specific lists
RDC 359/2020
RDC 57/2009

Multiple API-related Fully centralised assessment

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guidelines of APIs
Initial submission

I. Associated CADIFA application:

a. With confidentiality restrictions;

b. No confidentiality restrictions;
*Priority*

II. Standalone CADIFA application:

c. Expression of interest from manufacturers;

d. Public invitation issued by the BoD (ANVISA).

*Published on ANVISA’s website*

Holder + CADIFA Number + Status 6
Submission procedure
Example 1:
• With confidentiality restrictions
• 1st submission
CADIFA

DIFA Holder
AP RP

API-related deficiencies
(120 days)

Marketing
authorisation AP
Declaration
AP applicant

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Submission procedure
Example 2:
• With confidentiality restrictions
• 2nd/3rd […] submissions
CADIFA

DIFA Holder

Marketing
authorisation + AP
AP Declaration
applicant
CADIFA CADIFA

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DIFA - Submission procedure
Example 3:
• With no confidentiality restrictions

CADIFA
CADIFA

Marketing
authorisation applicant
FULL
DIFA Holder

API-related deficiencies
(120 days)

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DIFA - Submission procedure
Example 4:
• Expression of interest

Expression of Interest ANVISA’s request Submission

CADIFA

DIFA Holder
AP RP

API-related deficiencies
(120 days) 10
API-Related Changes

RDC 359 – Annex II EDQM (revision CEPs)

Change application
Notify associated MA holders
(according to RDC 359/2020, art. 59)

DIFA Holder
API
variation Is the change major or are there
changes to the information
If disclosed in the CADIFA?

API-related
approved
deficiencies No
(120 days)
Yes

A new version of the CADIFA is issued. No further action

The MA holder must submit a is necessary from
variation to the MA (Updated CADIFA) the MA holder
CADIFA

CADIFA
I. Number and issue date.

II. API, DCB, CAS.

III. Name and address of DIFA Holder.

IV. Name and address of manufacturing sites.

V. API Specification and, if applicable,

compendial reference.

VI. Container closure system.

VII. Storage conditions.

VIII. Retest period or shelf-life.

IX. Declaration of access.

Administrative procedures – Submission format

• DIFA holders will use ANVISA Submission Systems

• Electronic submission (non-eCTD)

• Module 1 + Module 2 (optional) + Module 3

• Non-electronic submission

• Guia 24/2019 (ICH M4)

• Module 1 + Module 2 + Module 3

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Administrative procedures – CADIFA Guidance

• Initial submission

• Change application

• Response

• Additional information

• Closure LINK
• Suspension (by DIFA
holder)

• Closure (by DIFA holder)

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Adoption of ICH guidelines (*pertaining to APIs*)

• ICH M4Q (3.2.S)

• ICH Q1_
• ICH Q2
• ICH Q3A With RMS

• ICH Q3C
• ICH Q3D (*RDC 359/2019 - Annex I*)
• ICH Q6A
• ICH Q11 No RMS

• ICH M7
CADIFA - Suspension & Withdrawal

• Documental and/or GMP related issues.

• Severity of the issue and recurrence will determine whether a CADIFA

will be suspended or withdrawn by ANVISA.

• A MA application associated with a suspended/withdrawn CADIFA will

preclude the MA from being granted

• Measures of interest to public health regarding the API and the drug
products associated with a suspended/withdrawn CADIFA might be
undertaken (e.g. suspension of importation or manufacture).

• A CADIFA may also be suspended or withdrawn by its holder.

RDC 362/2020 - GMP

• Risk assessment-based inspections programme

• No change regarding GMP requirements (RDC 69/2014, ICH Q7)

• Scope: foreign API manufacturers.

• A GMP Certificate of the API manufacturer issued by ANVISA will be a

requirement for a marketing authorisation or addition of API
manufacturer (RDC 361/2020).
GMP - RDC /

• The GMP Certificate will be issued in one of three ways:

Inspection conducted by ANVISA

Risk assessment
+
Inspection conducted by an authority recognised as
equivalent by ANVISA

Risk assessment
RDC 318/2019

• Long term stability (for room temperature):

Storage condition Stability condition
30°C±2°C/75%RH±5%RH
Room temperature (between 30°C±2°C/70%RH±5%RH
15°C e 30°C)
30°C±2°C/65%RH±5%RH
Room temperature (between
15°C e 25°C) 25°C±2°C/60%RH±5%RH

• Forced degradation and photostability are a requirement

COIFA (API Department) website

https://www20.anvisa.gov.br/coifaeng/

http://portal.anvisa.gov.br/english/api

TO BE UPDATED...

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Thank you for your attention!

[email protected]

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